Osteoporosis is a bone-wasting disease in which there is an imbalance or uncoupling between the rate of bone formation and resorption resulting in a decrease in total bone mass. As a result of this decrease in bone mass the skeleton becomes weakened and unable to bear the normal weight-bearing stresses. The effects of osteoporosis are generally seen in the weight-bearing part of the skeleton, especially the spine and hips, which can fracture in the absence of trauma. Osteoporosis affects about 24 million people in the United States and 200 million worldwide and is blamed for 2.5 million fractures a year in elderly women. The American Medical Association estimates that 25% of white women will suffer fractures of the hip or spine in their lifetime as a result of osteoporosis.
The current therapies for postmenopausal osteoporosis consist of treatments which are for the most part preventative; estrogen replacement, bisphosphonates, vitamin D metabolites and calcium supplements act to inhibit bone resorption associated with the onset of menopause. Estrogen replacement in these patients is quite effective in reducing further loss of bone mass but it does not induce an increase in bone mass which is needed to reduce fracture risk and pain. These treatments have little utility in the treatment of those patients with existing osteoporosis-induced loss of bone mass who have a high fracture risk and back/joint pain. Post-menopausal women with vertebral bone mass of less than 100 mg/cc would be considered below the "fracture threshold" and would be candidates for treatment with an agent which would increase bone mass and thereby restore lost bone. The present invention focuses on agents which are useful in treating bone wasting diseases by increasing an individuals bone mass and thus reducing or eliminating fracture risk. The therapeutic need for this type of agent is clearly present, especially when one considers the poor patient compliance associated with estrogen replacement therapies.
U.S. Pat. No. 4,610,807 disclosed diethyl 3-trifluoromethylbenzylphosphonate. The compound is not specifically claimed or characterized in the patent but apparently is used in situ as a crude synthetic intermediate towards unrelated compounds with non-medicinal use (fabric whitener). Acids were neither disclosed nor claimed in this reference. Isomeric ortho and para trifluoromethylbenzylphosphonates are similarly disclosed as the esters.
U.S. Pat. No. 2,917,533 discloses several substituted benzylphosphonic acids and esters with utility claims of antihistaminic, antibacterial and herbicidal or plant growth regulatory activity. No 3-CF.sub.3 analog is described.